Myocardiac infarction is a condition of irreversible necrosis of heart muscle that results from prolonged ischemia. The infarct zone comprising a damaged myocardiac tissue are infiltrated with non-contracting scavenger cells and ultimately are replaced with scar tissue. This fibrous scar does not significantly contribute to the contraction of the heart. Cardiac cells do not divide to repopulate the damaged region, the region will fill with connective tissue produced by invading fibroblasts. Fibroblasts produce extracellular matrix components of which collagen is the most abundant. Neither the fibroblasts themselves nor the connective tissue form contractile tissue. Thus, molecular and cellular cardiomyoplasty research has evolved to directly address myocardial necrosis.
Conventionally, cellular cardiomyoplasty are performed by transplanting cells into the damaged myocardium with the goal of restoring its contractile function. In the methods, myoblast cells and hematopoietic stem cells are often used as the transplanting cells in order to cure the damaged myocardium. Myoblast cells are prepared by allowing the established cell lines to be induced, but such cells are typically rejected from the human recipient.
For example, Nature 428, 668-673, 2004 April, reported hematopoietic stem cells adopt only traditional hematopoietic fates based on the study of the ability of hematopoietic stem cells to regenerate myocardium in an infarct model. Also, Cell, vol. 119, Issue 4, 12 Nov. 2004, pages 543-554, reported muscle-engrafted cells from marrow and/or circulation localizes to the same anatomic compartment as myogenic satellite cells, but they displayed no intrinsic myogenicity. It further reported functional adult myogenic progenitors did not arise from hematopoietic or other bone marrow or circulating precursors.
Furthermore, molecular cardiomyoplasty has developed because fibroblasts can be genetically manipulated. For example, Tam et al., J. Thoracic and Cardiovascular Surgery, 918-924 (1995) used MyoD which is one of myogenic determination genes expressing retrovirus in vitro for fibroblast to myoblast conversion. However, its viability has not been demonstrated in vivo.
On the other hand, secreted frizzled-related protein (SFRP) family is known for having a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzled proteins, and acts as soluble modulators of Wnt signaling. Among the SFRP family, SFRP2 and SFRP4 are related to signal cascade in apoptosis, which is reported in Cancer Res. 65 (3), 743-748 (2005), and J. Biol. Chem. 279 (15), 14602-14609 (2004). Furthermore, other molecules involved in apoptosis include Midkine (MDK), Pleiotrophin (PTN) and Thymosin beta-10 (TB10) (J Med Dent Sci. 46 (1):45-51 (1999), and J Biol Chem. 277 (39), 35862-8 (2002), J. Biol. Chem. 280 (40), 340003-34007 (2005)).
Pleiotrophin (PTN) and midkine (MDK) are two members of developmentally regulated cytokines showing very similar three-dimensional structure with approximately 50% identity in amino acid sequences. They are highly conserved through Drosophila to man and are originally implicated in neural development, neurodegenerative diseases and certain form of cancer. PTN and MDK are localized in the radial glial processes of the embryonic brain, along which neural stem cells migrate and differentiate (Cancer Letter. 2004; 204:127-143, and Development. 1995; 121:37-51).
Interestingly, both proteins show mitotic, anti-apoptotic, and angiogenic activities, which are the basic properties required for the regeneration of injured tissues, not only in developing neural tissues but also in adult brain (Cancer Letter. 2004; 204:127-143, Development. 1995; 121:37-51, and Gene Therapy. 2005; 12:487-493). Furthermore, some reports have suggested the expression and their reparative capabilities in injured extra-neural organs including liver and heart (Liver Int. 2004; 24:484-491, Biochem Biophys Res Commun. 2005; 332:1146-1152, and Anticancer res. 1998; 18:145-152). In addition, Anticancer res. 1998; 18:145-152 and J. Immunol. 2001; 167:3463-3469 reported that developmentally regulated cytokines, PTN and MDK, are induced in stressed adult organs such as ischemic heart and kidney.
However, the role for these molecules of SFRP2, SFRP4, MDK, PTN, and TB10 in the damaged myocardium, and their therapeutic potential for the ischemic cardiomyopathy ware not well known.